The present invention provides for a novel method of treating polycystic ovary syndrome. Further, the present invention is directed to a method of improving fertility and the response to in vitro fertilization (I.V.F.) by employing a 5.alpha.-reductase type 1 inhibitor. The present invention also provides for a method of manufacture of a medicament useful for treating polycystic ovary syndrome and a method of manufacture of a medicament usefull as an adjunct in I.V.F. The present invention also provides for compositions useful in the method of treating polycystic ovary syndrome and useful as an adjunct in I.V.F.
Polycystic ovary syndrome (PCOS), also known as Stein-Leventhal syndrome, is characterized by menstrual irregularity and hirsutism and is a common cause of anovulatory infertility. The biochemical abnormalities are a high concentration of plasma luteinising hormone (LH) or a high LH/follicle stimulating hormone (FSH) ratio and high concentrations of androgens (testosterone and/or androstenedione and/or dehydroepiandrosterone (DHEA)). The increased androgens can be secreted by the ovary and/or the adrenal gland. Clinical manifestations of PCOS include amenorrhea, hirsutism acanthosis nigricans, acne and obesity. PCOS appears to account for about 75% of anovulatory infertility.
The chronic anovulation typical of PCOS results in an increased number of atretic follicles (which become cysts) and increased interstitial tissue in the stroma of the ovaries.
Under normal conditions, women produce a single dominant follicle that participates in a single ovulation each menstrual cycle. The process begins when a cohort of primordial follicles is recruited to initiate growth. Successive recruitment gives rise to the primary, secondary, tertiary and graafian follicles present in the ovaries. The ability to become a dominant follicle is not a characteristic shared by all follicles, and those that lack the property die by atresia due to increased androgens. In the human female, only about 400 of the original 7 million follicles survive atresia and give rise to dominant follicles.
In patients with PCOS, the process of folliculogenesis does not proceed normally. The initial steps, recruitment and growth to the small graafian stages, are functioning in PCOS, but the terminal step, the selection of dominant follicles that can ovulate, does not occur regularly. Viable follicles seldom develop beyond about the 6 mm stage. In some unexplained way, this condition leads to the accumulation of large numbers of small graafian follicles (commonly referred to as cysts) in which the theca interstitial cells (TIC) produce abnormally large amounts of androgen, but the granulosa cells (GC) fail to express the aromatase enzyme and aromatize the androgen substrate to estradiol. Consequently, a state of continued hyperandrogenism results. The problem is self-perpetuating in part because the atretic follicle becomes an androgenic follicle by a "default" mechanism: because of low aromatase activity in atretic follicles, androstenedione is preferentially metabolized to testosterone and thence to dihydrotestosterone within the ovary.
The human ovarian stromal, thecal and granulosa cell compartments each contain 5.alpha.-reductase activity. In the rat the 5.alpha.-reduced androgens 5.alpha.-androstane-3,17-dione (5.alpha.-A) and dihydrotestosterone (DHT) are competitive inhibitors of aromatase activity. This is likely to occur in humans as well, and therefore the 5.alpha.-reduced metabolites may lead to decreased aromatase activity, increased androgen secretion and follicular atresia.
Agarwal et al. "A Mechanism for the Suppression of Estrogen Production in Polycystic Ovary Syndrome" J. Clin Endocrinology & Metabolism 81(10):3686-3691 (1996), propose that polycystic ovary syndrome follicular fluid contains abnormally high 5.alpha.-A and/or DHT concentration that can inhibit aromatase activity. They conclude that 5.alpha.-A is the primary inhibitor of aromatase activity in PCOS follicular fluid.
Stewart et al. "5.alpha.-reductase activity in polycystic ovary syndrome" The Lancet 335:431-433 (1990) investigated the hypothesis that in PCOS increased cortisol metabolism stimulates corticotropin-mediated androgen excess. They proposed that enhanced activity of 5.alpha.-reductase is the fundamental defect in many patients with PCOS. The enzyme abnormality is proposed to mediate both hirsutism and enhanced hepatic cortisol metabolism. A concomitant increase in corticotropin secretion in women with PCOS is hypothesized to keep plasma cortisol concentrations normal, but at the expense of androgen excess. This hypothesis likely provides another mechanism, via the adrenal, in which the 5.alpha.-reductase activity contributes to PCOS.
Presently polycystic ovary syndrome is treated with GnRH analogues, oral contraceptives, steroids (such as prednisone) and/or antiandrogens. These antagonize androgens or decrease the whole H-P-G or H-P-Adrenal axes. None of the treatments currently employed corrects the underlying problem of the hyperandrogenic production by the ovarian follicles. Further, each of the currently employed treatments has significant side effects including: hypoestrogenism (GnRH analogues), menstrual irregularity (spironolactone, an antiandrogen), and headaches, bloating and the rare occurrence of blood clots associated with oral contraceptives. Steroids also have significant side effects such as adrenal suppression, obesity, striae, hypertension, etc.
The present invention relates to methods of treating polycystic ovary syndrome. Further, the present invention is directed to a method of improving fertility and the response to in vitro fertilization (I.V.F.) by employing a 5.alpha.-reductase type 1 inhibitor. It has now been found that a 5.alpha.-reductase type 1 inhibitors of structural formula I: ##STR2## are useful for the treatment of polycystic ovary syndrome and for improving fertility and the response to in vitro fertilization.
The enzyme 5.alpha.-reductase catalyzes the reduction of several androgens including: testosterone (T) to the more potent androgen, 5.alpha.-dihydrotestosterone (dihydrotestosterone" or DHT), as shown below: ##STR3##
5.alpha.-reductase also catalyzes the reduction of androstenedione (A) to androstanedione (5.alpha.-A), as shown below: ##STR4## and the reduction of progesterone to dihydroprogesterone, as shown below: ##STR5##
There are two isozymes of 5.alpha.-reductase in humans. Andersson, et al., Proc. Natl. Acad. Sci. USA, 87:3640-44 (1990); Andersson, et al., Nature, 354, 159-61 (1991). The isozymes, usually called Type 1 and Type 2, exhibit differences in their biochemical properties, genetics, and pharmacology. Both isozymes are now the subject of considerable research and it has been found one isozyme (type 1) predominates in he sebaceous glands of facial skin and skin tissue and that the other (type 2) predominates in the prostate.
Finasteride (17.beta.-(N-tert-butylcarbamoyl)-3-oxo-4-aza-5.alpha.-androst-1-en-3-one) as shown below, is a potent inhibitor of the human type 2 enzyme. ##STR6## Under the tradename PROSCAR.RTM., finasteride is known to be useful in the treatment of hyperandrogenic conditions, see e.g., U.S. Pat. No. 4,760,071. Finasteride is currently prescribed for the treatment of benign prostatic hyperplasia (BPH), a condition affecting to some degree the majority of men over age 55. Finasteride's usefulness in the treatment of androgenic alopecia and prostatic cancer is described in the following documents: EP 0 285 382, published Oct. 5, 1988, EP 0 285 383, published Oct. 5, 1988 and Canadian patents 1,302,277 and 1,302,276.
There have been reports (e.g., Ciotta et al., Fertility & Sterility 64(2): 299-306, 1996 and Fruzetti et al., J. Clin. Endocrin. Metab. 79: 703-706, 1994) in the literature of administration of the type 2 inhibitor finasteride to women with hirsutism, with no observed menstrual changes. Further, it has been reported that women with type 2 5.alpha.-reductase deficiency have normal menstrual cycles. This suggests that the type 2 enzyme does not predominate in the ovary.
Haning, Jr., et al., J. Steroid Molec. Biol. 59(2): 199-204 (1996) have recently reported that the human ovary apparently expresses mRNA for 5.alpha.-reductase type 1.
It has been presently found that the type 1 5.alpha.-reductase inhibitors of the present invention are useful in the treatment of polycystic ovary syndrome and in improving fertility and the response to in vitro fertilization.